title: What is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure?
abstract: BACKGROUND
  Paracetamol (acetaminophen) ingestion is the most frequent pharmaceutical overdose in the developed world. Metabolic acidosis sometimes occurs, but the acidosis is infrequently persistent or severe. A growing number of case reports and case series describe high anion gap metabolic acidosis (HAGMA) following paracetamol exposure with subsequent detection or measurement of 5-oxoproline (also called pyroglutamic acid) in blood, urine, or both. Typically 5-oxoprolinuria or 5-oxoprolinemia occurs in the setting of inborn genetic errors in glutathione metabolism. It is unknown whether 5-oxoprolinemia in the setting of paracetamol exposure reflects an acquired or transient derangement of glutathione metabolism or previously unrecognized genetic defects.
  
  
  OBJECTIVE
  We reviewed the published cases of 5-oxoprolinemia or 5-oxoprolinuria among patients with HAGMA in the setting of paracetamol exposure. Our goal was to identify any consistent features that might increase our understanding of the pathophysiology, diagnosis, and treatment of similar cases.
  
  
  METHODS
  We searched the medical literature using PUBMED and EMBASE from inception to 28 August 2013 applying search terms ("oxoproline" OR "pyroglutamic acid" AND "paracetamol" OR "acetaminophen"). The intersection of these two searches returned 77 articles, of which 64 involved human subjects and were in English. Two articles, one each in Spanish and Dutch, were reviewed. An additional Google Scholar search was done with the same terms. We manually searched the reference lists of retrieved articles to identify additional four relevant articles. We focused on articles including measured 5-oxoproline concentrations in urine or blood.
  
  
  RESULTS
  Twenty-two articles included quantified 5-oxoproline concentrations. Several additional articles mentioned only qualitative detection of 5-oxoproline in urine or blood without concentrations being reported. Our manual reference search yielded four additional articles for a total of 24 articles describing 43 patients with quantified 5-oxoproline concentrations. The cases varied widely in paracetamol dose, duration and circumstances of paracetamol exposure, presence, and degree of elevation in transaminase activities, and when reported observed blood, serum, or urine 5-oxoproline concentrations. Concomitant use of flucloxacillin, another medication associated with oxoprolinemia or oxoprolinuria, confounded several of the cases. No clear dose-response relationship existed between the quantity of paracetamol ingested and the observed concentrations of 5-oxoproline. Clinical outcomes, including mortality, varied with no clear relationship to 5-oxoproline concentrations.
  
  
  CONCLUSIONS
  In rare cases, HAGMA in the setting of paracetamol exposure is attributable to 5-oxoprolinemia. Clinicians should first exclude commoner and treatable causes of HAGMA, such as lactic acidosis, co-ingested drug administration, and ketoacidosis. It is likely that the propensity for HAGMA following paracetamol exposure may be genetically determined. The effects of acetylcysteine on 5-oxoproline concentrations or clinical outcome are unknown. When HAGMA is diagnosed, the 5-oxoproline concentration and the glutathione synthetase activity should be measured.
authors.affiliation: Division of Emergency Medicine, Washington University School of Medicine , St. Louis, MO , USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Liss
authors.forename: M S
authors.initials: MS
authors.lastname: Paden
authors.forename: E S
authors.initials: ES
authors.lastname: Schwarz
authors.forename: M E
authors.initials: ME
authors.lastname: Mullins
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000111:Acetylcysteine / Q000378:metabolism / Q000627:therapeutic use; D000138:Acidosis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism / Q000503:physiopathology; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D058633:Antipyretics / Q000506:poisoning*; D004198:Disease Susceptibility; D016166:Free Radical Scavengers / Q000378:metabolism / Q000627:therapeutic use; D005981:Glutathione Synthase / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D011761:Pyrrolidonecarboxylic Acid / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012720:Severity of Illness Index
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D016166:Free Radical Scavengers; D000082:Acetaminophen; D005981:Glutathione Synthase; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine